Surfactant Protein B Deficiency via the SFTPB Gene

Surfactant Protein B (SP-B) deficiency is a severe respiratory disorder due to dysfunction of surfactant composition. Surfactant is a lipid and protein mixture lining the lung tissue that lowers alveolar surface tension and prevents atelectasis during expiration. Loss of surfactant function results in alveoli collapse following expiration leading to shortness of breath and impaired oxygen delivery in the lung. In severe forms, respiratory failure occurs shortly after birth with infants requiring mechanical ventilation and lung transplantation for survival (Nogee et al. 2000; Tredano et al. 2003). SP-B deficiency patients fail to respond to surfactant replacement or corticosteroid therapy. Patients with milder forms of SP-B deficiency present with gradual hypoxemia, failure to thrive, and tachypnea (Ballard et al. 1995). Genetic testing is helpful in the differential diagnosis of SP-B deficiency from other surfactant deficiencies, respiratory infections, cardiac disorders with obstructed pulmonary venous return, and other respiratory distress syndromes (Hamvas 2006).

SF-B deficiency is inherited in an autosomal recessive manner through pathogenic variants in the SFTPB gene. Surfactant dysfunction may also be inherited in an autosomal dominant manner through pathogenic variants in the SFTPC and NKX2.1 genes or an autosomal recessive manner through pathogenic variants in the ABCA3 gene (Hamvas 2006). In the SFTPB gene, the c.397delCinsGAA (p.Pro133Glufs*95), commonly referred to as 121ins2, is the most frequently observed pathogenic variant and accounts for over half of cases to date (Nogee et al. 2000). The majority of pathogenic variants lead to complete loss of SFTPB function and include splice site, nonsense, insertion/deletions resulting in a frameshift, and missense changes causing a loss of protein stability (Hamvas 2006; Nogee et al. 2000; Tredano et al. 2003). In rare occasions, partial SF-B deficiency has been seen in individuals with missense variants and results in a milder form of disease (Ballard et al. 1995). Pathogenic variants have been reported throughout the coding region of the SFTPB gene. Multi-exonic deletions have been reported in two cases (Wegner et al. 2007; Schuerman et al. 2008). The SFTPB gene encodes surfactant protein B which is a hydrophobic protein that enhances surface tension to prevent collapse of airways following expiration (Hamvas 2006).

In a series of 32 affected infants with a diagnosis of SP-B, pathogenic variants in the SFTPB gene were identified in all cases. Sixteen were homozygous for c.391delCinsGAA, 10 compound heterozygous with c.391delCinsGAA and a second pathogenic variant, and 6 homozygous for other pathogenic variants (Nogee et al. 2000). Analytical sensitivity is >95% for detection of causative variants in the SFTPB gene by sequencing. Multi-exonic deletions have been found in two cases (Wegner et al. 2007; Schuerman et al. 2008).

This test provides full coverage of all coding exons of the SFTPB gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).